N ‐Linked Glycosylated β ‐Peptides Are Resistant to Degradation by Glycoamidase A

β ‐Peptides are resistant to degradation by a variety of proteolytic enzymes that rapidly degrade natural α ‐peptides. This is one of many characteristics that make β ‐peptides an attractive class of compounds for drug discovery efforts. To further understand the molecular recognition properties of β ‐peptides and the ability of enzymes to degrade them, we have synthesized a series of N‐ linked glycosylated β ‐ and α ‐peptides, and tested their stability towards a glycosidase. We found that glyco‐ β ‐peptides that contain N‐ acetylglucosamine ( 1 ) or N,N ‐diacetylchitobiose ( 2 ) are completely stable to degradation by glycoamidase A. In comparison, the glyco‐ α ‐peptides 3 and 4 containing N ‐acetylglucosamine or N,N ‐diacetylchitobiose are degraded. Inhibition experiments using increasing concentrations of a glyco‐ β ‐peptide fail to inhibit degradation of the corresponding glyco‐ α ‐peptide, even when the glyco‐ β ‐peptide is at a 128‐fold higher concentration than the glyco‐ α ‐peptide. Evidently, the glyco‐ β ‐peptides have a much weaker affinity for the active site of the glycosidase than the corresponding glyco‐ α ‐peptide. These and the results with proteolytic enzymes suggest that the additional CH 2 group introduced into the α ‐amino acid residues causes β ‐peptides not to be recognized by hydrolytic enzymes. The results described herein suggest the potential of β ‐peptides that are functionalized with carbohydrates for biological and biomedical investigations, without having to be concerned about the carbohydrate being removed.